Hithertofore, as 3,4,5,6-tetrahydrophthalimide derivatives having an herbicidal activity, for example, Japanese Patent Publication (Kokai) Nos. 54-154737, 55-157546 (Japanese Patent Publication No. 63-13981), 59-51250, 60-252457, 61-43160, or U.S. Pat. No. 4,613,675 have been known, but the compounds having a cycloalkyloxy group at the 5-position of the phenyl ring on the nitrogen atom thereof have not been known.
Also, it is conventionally known that the 3,4,5,6-tetrahydrophthalamic derivatives having a carboxylic acid residual group and an amido group which are synthesized by reacting an aniline derivative with 3,4,5,6-tetrahydrophthalic anhydride (for example, the compounds disclosed in Japanese Patent Publication (Kokai) Nos. 48-44425, 54-125640 and 59-67255) exhibit a herbicidal activity, but the 3,4,5,6-tetrahydroisophthalimide hydroxy derivatives represented by the structure of the general formula (V') having a cycloalkyloxy group at the 5-position of the phenyl ring on the nitrogen atom thereof have not been known.
Further, as 3,4,5,6-tetrahydroisophthalimide derivatives, for example, the-compounds disclosed in Japanese Patent Publication (Kokai) No. 53-23962, Japanese Patent Publication No. 3-69907, Japanese Patent Publication No. 4-7347, and U.S. Pat. No. 3,990,880 have been known, but the compounds having a cycloalkyloxy group at the 5-position of the phenyl ring on the nitrogen atom thereof have not been known.
Development of excellent herbicides is required for protecting important crops, for example, rice, soybean, corn, wheat or cotton or beat from weeds, and, further, increasing the productivity of these crops, and contributes to the labor-saving of the agricultural works and hence to the stabilization of the food economy. For such herbicides, development of agents having the following conditions is required.
That is, from the viewpoint of effects, agents having a broad herbicidal spectrum and at the same time a high safety to crops, and also having a high activity to perennial weeds which are difficult to remove are desirable, and, from the viewpoint of labor-saving of works, agents which are effective with a less number of treating times with the agent, and the effect thereof lasts for an appropriate period of time are desirable.
The conventionally known 3,4,5,6-tetrahydrophthalamide derivatives or 3,4,5,6-tetrahydroisophthalimide derivatives per se exhibits good herbicidal effects, but it cannot be said that these derivatives necessarily satisfy the desirable requirements. Further, the above-described known compounds exhibit markedly different strength in the herbicidal activity or selectivity to crops by slight difference in the structure thereof (for example, the type and position of substituents), and, therefore, it is difficult to predict herbicidal activities and selectivities of new compounds merely from the similarity in the chemical structure.
The present invention provides compounds which exhibit an excellent herbicidal activity in the treatment at a low amount and a high safety, and which are further useful as active ingredients of herbicides having an excellent selectivity to the crops.
As a result of extensive studies from the above viewpoints, the present inventors found that the 3,4,5,6-tetrahydrophthalaimide derivatives in which a cycloalkyloxy group as a substituent has been introduced into the 5-position of the phenyl ring, represented by the general formula (I): ##STR5## wherein X.sup.1, X.sup.2, R.sup.1, R.sup.2, R.sup.3 and R.sup.4 have the same meanings as above, and the 3,4,5,6-tetrahydroisophthalimide derivatives in which a cycloalkyloxy group as a substituent has been introduced at the 5-position of the phenyl ring, represented by the general formula (V): ##STR6## wherein X.sup.1, X.sup.2, R.sup.1 and R.sup.2 have the same meanings as above, have a high herbicidal activity against weeds by the treatment at a low dose and, also, a markedly reduced detrimental effect by the agent on main crops.
The compounds of the present invention exhibit markedly excellent herbicidal activities in the treatment at a low dose in the stem-foliar treatment and the soil treatment in the field on various troublesome weeds, for example, broad leaf weeds such as Chenopodium album, Amaranthus viridis, Abutilon theophrasti, Stellaria media, Persicaria longiseta and Ambrosia elatior, and grass weeds such as Echinochloa crus-galli, Setaria viridis, Digitalia ciliaris, Eleusine indica and Alopecurus aequalis, but do not exhibit any troublesome detrimental effect by the agent on main crops, e.g., broad leaf crops such as soybean, cotton and beat, grass crops such as corn and wheat.
Also, the compounds of the present invention exhibit markedly excellent herbicidal activities in the treatment at a low dose on various troublesome weeds in the paddy field, for example, grass weeds such as Echinochloa oryzicola and Echinochloa crus-galli, broad leaf weeds such as Lindernia pyxidaria, Rotala indica, Callitriche fallax and Monochoria vaginalis, Cyperus weeds such as Scirpus juncoides, Eleocharis acicularis, Cyperus difformis, Cyperus serotinus and Eleocharis kuroguwai, and Sagittaria pygmaea, whereas these compounds exhibit only very slight detrimental effects by the agent on the transplanted rice plants in the paddy field.
Such a high selectivity of the compounds of the present invention can not be totally expected from conventional 3,4,5,6-tetrahydrophthalamide derivatives, and this characteristic is apparently brought about by introducing a cycloalkyloxy group into the 5-position of the phenyl ring thereof.
In the compounds (I) and (V) of the present invention, examples of the halogen atoms represented by X.sup.1 and X.sup.2 include a fluorine atom, a chlorine atom and a bromine atom.
Examples of the cycloalkyl group represented by R.sup.1 include a cyclopropyl group, a cyclopentyl group, a cyclohexyl group, and a cyclooctyl group, and these groups may be substituted with a lower alkyl group having from 1 to 4 carbon atoms such as a methyl group, an ethyl group and an isopropyl group, or a halogen atom such as a fluorine atom and a chlorine atom.
In the compounds (I) of the present invention, the alkyl group represented by R.sup.3 and R.sup.4 may be a straight chain or a branched chain and further may have an alicyclic structure on the chain, and examples thereof include a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a sec-butyl group, a tert-butyl group, a pentyl group, a neopentyl group, an isopentyl group, a tert-pentyl group, a 1,2-dimethylpropyl group, a 1-methylbutyl group, a hexyl group, an isohexyl group, a heptyl group, a 1-ethylhexyl group, an octyl group, a decyl group, an undecyl group, a dodecyl group, a cyclopropylmethyl group, a cyclohexylmethyl group, a cyclohexenylmethyl group, a 1-adamantylmethyl group and a myrtanyl group.
These alkyl groups may be substituted with one or more of a halogen atom, a lower alkoxy group, a hydroxy group, a carboxyl group, a lower alkyloxycarbonyl group, a substituted amino group and a cyano group, and examples of these substituted alkyl groups include a 2-chloroethyl group, a 2-bromoethyl group, a 3-fluoropropyl group, a 3-bromopropyl group, a 3,3,3-trifluoropropyl group, a 2-hydroxyethyl group, a 1-hydroxymethyl-2-methylpropyl group, a 1-hydroxymethyl-2-methylbutyl group, a 1-hydroxymethyl-3-methylbutyl group, a 1,1-di(hydroxymethyl)ethyl group, a 1-hydroxymethyl-1-methylethyl group, a 1,5-dimethyl-5-hydroxyhexyl group, a 2-(2-hydroxyethoxy)ethyl group, a 2-methoxyethyl group, a 3-methoxypropyl group, a 1-methoxy-1-methylpropyl group, a 3-ethoxypropyl group, a 3-isopropoxypropyl group, a 3-propoxypropyl group, a 3-butoxypropyl group, a methoxycarbonylmethyl group, a 1-(methoxycarbonyl)ethyl group, a 1-(methoxycarbonyl)propyl group, a 2-methoxycarbonyl-2-methylpropyl group, a 1-methoxycarbonyl-3-methylbutyl group, a 1-methoxycarbonyl-2,2-dimethylpropyl group, an ethoxycarbonylmethyl group, a 2-ethoxycarbonyl-2-methylpropyl group, a 1-carboxyethyl group, a 1-carboxypropyl group, a 2-carboxy-2-methylpropyl group, a 1-carboxy-3-methylbutyl group, a 2-(memthoxycarbonyl)ethyl group, a 2-carboxyethyl group, a 6-carboxyhexyl group, a 4-carboxycyclohexylmethyl group, a 3-dimethylaminopropyl group, a 1-methyl-4-diethylaminobutyl group, a 1-ethoxycarbonyl-4-piperidyl group, and a cyanoethyl group.
Also, the above-described alkyl groups may be substituted with an aromatic group or an alicyclic heterocyclic group which may be substituted with one or more of a halogen atom, a lower alkyl group, a lower alkoxy group, a hydroxy group, a carboxyl group, a lower alkyloxycarbonyl group, a nitro group and a cyano group.
Specific examples of these substituted alkyl groups include a benzyl group, a chlorobenzyl group, a 3-chlorobenzyl group, a 4-chlorobenzyl group, a 4-t-butylbenzyl group, a 4-methylbenzyl group, a 4-methoxybenzyl group, a 1-phenylethyl group, an R-(+)-1-phenylethyl group, an S-(-)-1-phenylethyl group, a 1-(4-chlorophenyl)ethyl group, a 1-(4-methoxyphenyl)ethyl group, a 2-phenylethyl group, a 2-(3,4-dimethoxyphenyl)ethyl group, a 1-methyl-1-phenylethyl group, a 1-methyl-1-(3-chlorophenyl)ethyl group, a 1-methyl-1-(3-fluorophenyl)ethyl group, a 1-methyl-1-(3-trifluoromethylphenyl)ethyl group, a 1-methyl-1-(4-methylphenyl)ethyl group, a 1-methyl-2-(2-hydroxyphenyl)ethyl group, a 1-methyl-1-(4-chlorophenyl)ethyl group, a 1-methyl-1-(4-fluorophenyl)ethyl group, a 1-methyl-1-(4-bromophenyl)ethyl group, a 1-methyl-1-phenylpropyl group, a 1-methyl-1-(4-chlorophenyl)propyl group, a 1-methyl-1-(4-methoxyphenyl)ethyl group, a 1-methyl-1-(2,4-dichlorophenyl)ethyl group, a 1-(1-naphthyl)ethyl group, a 1-(2-naphthyl)ethyl group, a (2-naphthyl)methyl group, a 2-pyridylmethyl group, a 2-(2-pyridyl)ethyl group, a 2-picolyl group, a 3-picolyl group, a furfuryl group, a tetrahydrofurfuryl group, a 2-thiophenemethyl group, a 2-(1-methyl-2-pyrrol-2-yl)ethyl group, a 2-(1-methylpyrrolidinyl)ethyl group, a 2-(1-pyrrolidinyl)ethyl group, a 2-morpholinoethyl group, a 3-morpholinopropyl group and a 2-piperidinoethyl group.
Examples of the cycloalkyl group represented by R.sup.3 and R.sup.4 include a cyclopropyl group, a cyclopentyl group, a cyclohexyl group, a cyclooctyl group, a 2-norbornyl group, a norbornen-2-yl group, a 2-bicyclo[3.2.1]octyl group, a 3-noradamantyl group, a 1-adamantyl group and a 2-adamantyl group. These cycloalkyl groups may be substituted with a lower alkyl group, a halogen atom, a hydroxy group, or an amino group, etc., and examples thereof include a 2-methylcyclohexyl group, a 2-aminocyclohexyl group, a 2-hydroxycyclohexyl group, and a 1-(hydroxymethyl)cyclopentyl group.
Examples of the alkenyl group or the alkynyl group represented by R.sup.3 and R.sup.4 include an allyl group, a methallyl group, a crotyl group, a purenyl group, a propargyl group and a 1-butyn-3-yl group. Also, these alkenyl groups and alkynyl groups may be substituted with a halogen atom such as a fluorine atom or a chlorine atom.
Examples of the aryl group represented by R.sup.3 and R.sup.4 includes a phenyl group and a naphthyl group. These aryl groups may be substituted with a lower alkyl group, a halogen atom, a lower alkoxy group, a hydroxymethyl group, a trifluoromethyl group, a carboxy group, a cyano group, etc., and examples thereof include a 2-chlorophenyl group, a 2-fluorophenyl group, a 4-chlorophenyl group, a 4-fluorophenyl group, a 4-tert-butylphenyl group, a 4-methylphenyl group, a 4-isopropylphenyl group, a 2-hydroxymethylphenyl group, a 3-hydroxymethylphenyl group, a 4-hydroxymethylphenyl group, a 3-chloro-4-cyanochlorophenyl group, a 4-carboxy-3-chlorophenyl group, a 5-chloro-2-trifluoromethylphenyl group, a 4-chloro-2-trifluoromethylphenyl group, a 2-chloro-5-trifluoromethylphenyl group and a 4-chloro-3-trifluoromethylphenyl group.
Examples of substituted or unsubstituted allcyclic heterocyclic ring formed with the nitrogen atom to which R.sup.3 and R.sup.4 are bonded include those illustrated in terms of the amines represented by the corresponding general formula (III), as well as aziridine, azetidine, piperidine, pyrrolidine, piperazine, morpholine, thiomorpholine, 2-pyrroline, 3-pyrroline, 1,2,3,6-tetrahydropyridine, pyrazolidine, pyrazoline, 1,2-piperazine, 1,3-piperazine, thiazolidine, oxazolidine, isooxazolidine, tetrahydropyridazine and hexahydropyridazine.
These allcyclic heterocyclic rings may be substituted with a lower alkyl group, a phenyl group, a substituted phenyl group, a benzyl group, an acetyl group, a hydroxy group, a hydroxymethyl group, a carboxyl group, an acetamido group, a lower alkyloxycarbonyl group, etc., and examples thereof include, as specifically illustrated in terms of the amines (III), methylaziridine, 2,5-dimethylpyrrolidine, 3-hydroxypyrrolidine, proline, perhydroindole, 3-acetamidopyrrolidine, 4-carboxythiazolidine, 3,5-dimethylpiperidine, 3,3-dimethylpiperidine, isonipecotic acid, 3-hydroxypiperidine, 2,6-dimethylpiperidine, ethyl 2-pipecolate, ethyl 3-nipecotate, ethyl isonipecotate, 4-benzylpiperidine, 1-phenylpiperazine, 1-(2-methylphenyl)piperazine, 1-methylpiperazine, 1-benzylpiperazine, 1-(2-methoxyphenyl)piperazine, 1-(2-chlorophenyl)piperazine, 1-(2-fluorophenyl)piperazine, 1-(4-fluorophenyl)piperazine and 1-ethoxycarbonylpiperazine.
The amines (III) having a substituent as illustrated above are commercially available compounds or compounds which can be easily synthesized by a conventional process.
Processes for preparing the compounds of the present invention, 3,4,5,6-tetrahydrophthalamide derivatives (I), and the compounds of the present invention, 3,4,5,6-tetrahydroisophthalimide derivatives (V) which are also starting materials therefor are described below.
The compounds of the present invention represented by the general formula (I) can be prepared by reacting a 3,4,5,6-tetrahydrophthalimide derivative represented by the general formula (II): ##STR7## wherein X.sup.1, X.sup.2, R.sup.1 and R.sup.2 have the same meanings as defined above, with an amine represented by the general formula (III): ##STR8## wherein R.sup.3 and R.sup.4 have the same meanings as defined above. In this reaction, the compounds of the present invention (I) can be obtained in good yields by reacting generally 0.5 molar equivalent or more, preferably from 0.9 to 1.5 molar equivalent of the amine (III) to the 3,4,5,6-tetrahydrophthalimide derivative (II).
The reaction can be conducted in a solvent, for example, a halogenated hydrocarbon solvent such as methylene chloride, chloroform, carbon tetrachloride and chlorobenzene, a hydrocarbon solvent such as benzene, toluene, xylene, hexane, octane and cyclohexane, an ether solvent such as diethyl ether, dioxane, tetrahydrofuran and dimethoxyethane, a ketone solvent such as acetone and methyl ethyl ketone, an inert solvent such as acetonitrile, ethyl acetate and dimethylformamide, or a mixed solvent thereof.
The reaction temperature is generally selected from a range of from 0.degree. C. to 100.degree. C. The reaction time varies depending upon the type of reaction materials, and generally the reaction is completed within 5 minutes to 24 hours.
Also, the reaction can be carried out by adding a catalyst for the purpose of promoting the reaction. The catalyst which is generally used includes a basic compound such as triethylamine, N-methylmorpholine, pyridine, N,N-dimethylaniline, potassium carbonate and sodium carbonate.
The tetrahydrophthalimide derivatives represented by the above general formula (II) which are starting materials for the preparation of the compounds of the present invention can be easily prepared according to the process described in Japanese Patent Publication (Kokai) No. 4-164067. More specifically, these compounds can be prepared by reacting an aniline derivative represented by the general formula (VI): ##STR9## wherein X.sup.1, X.sup.2 and R.sup.1 have the same meanings as defined above, with a 3,4,5,6-tetrahydrophthalic anhydride represented by the general formula (VII): ##STR10## wherein R.sup.2 has the same meaning as defined above, in an organic solvent, preferably while heating at 50.degree. to 120.degree. C. (refer to Reference Example 17 and 18 described hereinafter).
Examples of the 3,4,5,6-tetrahydrophthalimide derivatives represented by the above-described general formula (II) which can be prepared as described above and which are starting materials for the preparation of the compounds of the present invention include N-(2-fluoro-4-chloro-5-cyclopropyloxyphenyl)-3,4,5,6-tetrahydrophthalimide , N-(2-fluoro-4-chloro-5-cyclopentyloxyphenyl)-3,4,5,6-tetrahydrophthalimid e, N-{2-fluoro-4-chloro-5-(2-methylcyclopentyl)oxyphenyl}-3,4,5,6-tetrahydrop hthalimide, N-{2-fluoro-4-chloro-5-(3-methylcyclopentyl)oxyphenyl)-3,4,5,6-tetrahydrop hthalimide, N-(2-fluoro-4-chloro-5-cyclohexyloxyphenyl)-3,4,5,6-tetrahydrophthalimide, N-{2-fluoro-4-chloro-5-(2-chlorocyclohexyl)oxyphenyl}-3,4,5,6-tetrahydroph thalimide, N-(2-fluoro-4-chloro-5-cyclooctyloxyphenyl)-3,4,5,6-tetrahydrophthalimide, N-(2-fluoro-4-bromo-5-cyclopropyloxyphenyl)-3,4,5,6-tetrahydrophthalimide, N-(2-fluoro-4-bromo-5-cyclopentyloxyphenyl)-3,4,5,6-tetrahydrophthalimide, N-{2-fluoro-4-bromo-5-(2-methylcyclopentyl)oxyphenyl}-3,4,5,6-tetrahydroph thalimide, N-{2-fluoro-4-bromo-5-(3-methylcyclopentyl)oxyphenyl}-3,4,5,6-tetrahydroph thalimide, N-(2-fluoro-4-bromo-5-cyclohexyloxyphenyl)-3,4,5,6-tetrahydrophthalimide, N-(2,4-dichloro-5-cyclopropyloxyphenyl)-3,4,5,6-tetrahydrophthalimide, N-(2,4-dichloro-5-cyclopentyloxyphenyl)-3,4,5,6-tetrahydrophthalimide, N-{2,4-dichloro-5-(2-methylcyclopentyl)oxyphenyl}-3,4,5,6-tetrahydrophthal imide, N-{2,4-dichloro-5-(3-methylcyclopentyl)oxyphenyl}-3,4,5,6-tetrahydrophthal imide, N-(2,4-dichloro-5-cyclohexyloxyphenyl)-3,4,5,6-tetrahydrophthalimide, N-(2 ,4-dichloro-5-cyclooctyloxyphenyl)-3,4,5,6-tetrahydrophthalimide, N-(2-fluoro-4-chloro-5-cyclopentyloxyphenyl)-3-methyl-3,4,5,6-tetrahydroph thalimide, N-(2-fluoro-4-chloro-5-cyclopentyloxyphenyl)-4-methyl-3,4,5,6-tetrahydroph thalimide, N-(2-fluoro-4-chloro-5-cyclopentyloxyphenyl)-4-chloro-3,4,5,6-tetrahydroph thalimide, N-{2-fluoro-4-chloro-5-(3-methylcyclopentyl)oxyphenyl}-3-methyl-3,4,5,6-te trahydrophthalimide, N-{2-fluoro-4-chloro-5-(3-methylcyclopentyl)oxyphenyl}-4-methyl-3,4,5,6-te trahydrophthalimide, N-(2-fluoro-5-cyclopentyloxyphenyl)-3,4,5,6-tetrahydrophthalimide, N-{2-fluoro-5-(2-methylcyclopentyl)oxyphenyl}-3,4,5,6-tetrahydrophthalimid e, N-{2-fluoro-5-(3-methylcyclopentyl)oxyphenyl-3,4,5,6-tetrahydrophthalimide , and N-(2-fluoro-5-cyclohexyloxyphenyl)-4-methyl-3,4,5,6-tetrahydrophthalimide.
Also, the compounds of the present invention represented by the general formula (I) can be prepared by reacting a 3,4,5,6-tetrahydroisophthalimide derivative which is a compound of the present invention represented by the general formula (IV): ##STR11## wherein X.sup.1, X.sup.2, R.sup.1 and R.sup.2 have the same meanings as defined above, with an amine presented by the general formula (III): ##STR12## wherein R.sup.3 and R.sup.4 have the same meanings as defined above. In this reaction, the compounds of the present invention (I) can be obtained in good yields by reacting generally 0.5 molar equivalent or more, preferably from 0.9 to 1.5 molar equivalent of the amine (III) to the 3,4,5,6-tetrahydroisophthalimide derivative (IV).
The reaction can be conducted in a solvent, for example, a halogenated hydrocarbon solvent such as methylene chloride, chloroform, carbon tetrachloride and chlorobenzene, a hydrocarbon solvent such as benzene, toluene, xylene, hexane, octane and cyclohexane, an ether solvent such as diethyl ether, dioxane, tetrahydrofuran and dimethoxyethane, a ketone solvent such as acetone and methyl ethyl ketone, an inert solvent such as acetonitrile, ethyl acetate and dimethylformamide, or a mixed solvent thereof.
The reaction temperature is generally selected from a range of from 0.degree. C. to 100.degree. C. The reaction time varies depending upon the type of reaction materials, and generally the reaction is completed within 5 minutes to 24 hours.
Also, the reaction can be carried out by adding a catalyst for the purpose of promoting the reaction. The catalyst which is generally used includes a basic compound such as triethylamine, N-methylmorpholine, pyridine, N,N-dimethylaniline, potassium carbonate and sodium carbonate.
Further, the tetrahydroisophthalimide derivatives of the present invention represented by the above general formula (IV) which are starting mterials of the compounds (I) of the present invention can be prepared according to the process shown by the following formulae: ##STR13## wherein X.sup.1, X.sup.2 and R.sup.1 have the same meanings as defined above.
More specifically, Step-1 is a step of reacting an aniline derivative presented by the general formula (VI) with a 3,4,5,6-tetrahydrophthalic anhydride represented by the general formula (VII) in an organic solvent at a low temperature to convert it into a 3,4,5,6-tetrahydroisophthalimidohydroxy derivative represented by the general formula (V').
The organic solvent used in the reaction of Step-1 may be any solvents which do not adversely affect the reaction, and examples of the solvent which can be used include ketones such as acetone, methyl ethyl ketone, methyl isobutyl ketone and cyclohexanone, aromatic hydrocarbons such as benzene, toluene, xylene, chlorobenzene and dichlorobenzene, aliphatic hydrocarbons such as hexane, heptane, octane and petroleum ether, ethers such as diethyl ether, diisopropyl ether, dioxane, tetrahydrofuran and ethylene glycol dimethyl ether, esters such as ethyl acetate, butyl acetate and methyl formate, nitriles such as acetonitrile and isobutyronitrile, carboxylic acids such as acetic acid and propionic acid, or a mixed solvent thereof.
The reaction temperature is selected between 0.degree. C. and 100.degree. C., but the reaction is preferably conducted at a low temperature below 50.degree. C. from the standpoint of good yields. After completion of the reaction, usual post-treatments are performed and, if necessary, the product can be purified by the procedure such as chromatography and recrystallization.
Generally, in the reaction of the aniline derivative represented by the general formula (VI) with the 3,4,5,6-tetrahydrophthalic anhydride represented by the general formula (VII), the reaction chemically provides a ring-opened 3,4,5,6-tetrahydrophthalamic acid derivative represented by the following general formula (VIII): ##STR14## wherein X.sup.1, X.sup.2, R.sup.1 and R.sup.2 have the same meanings as defined above, due to attack of the amino group to the carbonyl group of the acid anhydride, but, in the case of using the aniline derivative (VI) having a cycloalkyloxy group at the 5-position of the phenyl ring, it is considered that an intramolecular cyclization further occurs easily due to steric and electronic factors whereby the product is obtained as a more stable 3,4,5,6-tetrahydroisophthalimidohydroxy derivative represented by the general formula (V').
Step-2 is a step of reacting a 3,4,5,6-tetrahydroisophthalimidohydroxy derivative represented by the general formula (V') in the presence of a dehydrating agent in an organic solvent to produce a 3,4,5,6-tetrahydroisophthalimide derivative represented by the general formula (IV).
The organic solvent used in this step may be any solvents which do not adversely affect the reaction, and examples of the solvent which can be used include ketones such as acetone, methyl ethyl ketone, methyl isobutyl ketone and cyclohexanone, aromatic hydrocarbons such as benzene, toluene, xylene, chlorobenzene and dichlorobenzene, aliphatic hydrocarbons such as hexane, heptane, octane and petroleum ether, ethers such as diethyl ether, diisopropyl ether, dioxane, tetrahydrofuran and ethylene glycol dimethyl ether, esters such as ethyl acetate, butyl acetate and methyl formate, nitriles such as acetonitrile and isobutyronitrile, carboxylic acids such as acetic acid and propionic acid, or a mixed solvent thereof.
Examples of the dehydrating agent include carbodiimides such as dicyclohexylcarbodiimide, diisopropylcarbodiimide and diethylcarbodiimide, halogenating agents such as thionyl chloride, 2,4,6-triisopropylbenzenesulfonyl chloride, mesitylenesulfonyl chloride, phosphorus oxychloride and phosgene, and polyphosphoric acid esters. Although the amount of the dehydrating agent to be used is not limited, the use of about 1 to 3 molar equivalents relative to the starting material is preferred from the standpoint of good yields and easy post-treatment.
The reaction temperature is selected between -30.degree. and 100.degree., the reaction is preferably conducted at a low temperature of from about 0.degree. to room temperature from the standpoint of good yields. After completion of the reaction, usual post-treatments are performed and, if necessary, the product can be purified by the procedure such as chromatography and recrystallization.
Examples of the 3,4,5,6-tetrahydroisophthalimide derivatives represented by the above-described general formula (IV) which can be prepared as described above and which are starting materials for the preparation of the compounds of the present invention include N-(2-fluoro-4-chloro-5-cyclopropyloxyphenyl)-3,4,5,6-tetrahydroisophthalim ide, N-(2-fluoro-4-chloro-5-cyclopentyloxyphenyl)-3,4,5,6-tetrahydroisophthalim ide, N-{2-fluoro-4-chloro-5-(2-methylcyclopentyl)oxyphenyl}-3,4,5,6-tetrahydroi sophthalimide, N-{2-fluoro-4-chloro-5-(3-methylcyclopentyl)oxyphenyl)-3,4,5,6-tetrahydroi sophthalimide, N-(2-fluoro-4-chloro-5-cyclohexyloxyphenyl)-3,4,5,6-tetrahydroisophthalimi de, N-{2-fluoro-4-chloro-5-(2-chlorocyclohexyl)oxyphenyl}-3,4,5,6-tetrahydrois ophthalimide, N-(2-fluoro-4-chloro-5-cyclooctyloxyphenyl)-3,4,5,6-tetrahydroisophthalimi de, N-(2-fluoro-4-bromo-5-cyclopropyloxyphenyl)-3,4,5,6-tetrahydroisophthalimi de, N-(2-fluoro-4-bromo-5-cyclopentyloxyphenyl)-3,4,5,6-tetrahydroisophthalimi de, N-{2-fluoro-4-bromo-5-(2-methylcyclopentyl)oxyphenyl}-3,4,5,6-tetrahydrois ophthalimide, N-{2-fluoro-4-bromo-5-(3-methylcyclopentyl)oxyphenyl}-3,4,5,6-tetrahydrois ophthalimide, N-(2-fluoro-4-bromo-5-cyclohexyloxyphenyl)-3,4,5,6-tetrahydroisophthalimid e, N-(2,4-dichloro-5-cyclopropyloxyphenyl)-3,4,5,6-tetrahydroisophthalimide, N-(2,4-dichloro-5-cyclopentyloxyphenyl)-3,4,5,6-tetrahydroisophthalimide, N-{2,4-dichloro-5-(2-methylcyclopentyl)oxyphenyl}-3,4,5,6-tetrahydroisopht halimide, N-{2,4-dichloro-5-(3-methylcyclopentyl)oxyphenyl}-3,4,5,6-tetrahydroisopht halimide, N-(2,4-dichloro-5-cyclohexyloxyphenyl)-3,4,5,6-tetrahydroisophthalimide, N-(2,4-dichloro-5-cyclooctyloxyphenyl)-3,4,5,6-tetrahydroisophthalimide, N-(2-fluoro-4-chloro-5-cyclopentyloxyphenyl)-3-methyl-3,4,5,6-tetrahydrois ophthalimide, N-(2-fluoro-4-chloro-5-cyclopentyloxyphenyl)-4-methyl-3,4,5,6-tetrahydrois ophthalimide, N-(2-fluoro-4-chloro-5-cyclopentyloxyphenyl)-4-chloro-3,4,5,6-tetrahydrois ophthalimide, N-{2-fluoro-4-chloro-5-(3-methylcyclopentyl)oxyphenyl}-3-methyl-3,4,5,6-te trahydroisophthalimide, N-{2-fluoro-4-chloro-5-(3-methylcyclopentyl)oxyphenyl}-4-methyl-3,4,5,6-te trahydroisophthalimide, N-(2-fluoro-5-cyclopentyloxyphenyl)-3,4,5,6-tetrahydroisophthalimide, N-{2-fluoro-5-(2-methylcyclopentyl)oxyphenyl-3,4,5,6-tetrahydroisophthalim ide, N-{2-fluoro-5-(3-methylcyclopentyl)oxyphenyl-3,4,5,6-tetrahydroisophthalim ide, and N-(2-fluoro-5-cyclohexyloxyphenyl)-4-methyl-3,4,5,6-tetrahydroisophthalimi de.
Also, the aniline derivatives represented by the general formula (VI) which are starting materials for the production of the tetrahydrophthalimide derivatives (II) or the 3,4,5,6-tetrahydroisophthalimide derivative (IV) of the present invention can be prepared, for example, in accordance with the process of Reference Examples described in the specification of Japanese Patent Publication (Kokai) No. 4-164067, but they can also be prepared, for example, according to the process illustrated by the following reaction scheme (refer to Reference Examples 1 to 7 described hereinafter): ##STR15## wherein X.sup.1, X.sup.2 and R.sup.1 have the same meanings as defined above, and Z represents a removable group such as a halogen atom such as a bromine atom or an iodine atom or a sulfonyloxy group such as a p-toluenesulfonyloxy group, a benzenesulfonyloxy group and a methanesulfonyloxy group.
Further, the aniline derivatives represented by the general formula (VI) can be easily prepared by reacting a hydroxyaniline derivative represented by the general formula (X) (for example, Japanese Patent Publication No. 2-26622) and a cycloalkylating agent represented by the general formula R.sup.1 Z (IX) in the presence of a phase transition catalyst, for example, by reacting in a two-layer system of a sodium hydroxide aqueous solution and toluene under heating, or by reacting in the presence of a base, for example, potassium carbonate, in a solvent such as dimethylformamide under heating (refer to Reference Examples 8 to 16 hereinafter described). ##STR16## wherein X.sup.1, X.sup.2 and R.sup.1 have the same meanings as defined above, and Z represents a removable group such as a halogen atom such as a bromine atom or an iodine atom or a sulfonyloxy group such as a p-toluenesulfonyloxy group, a benzenesulfonyloxy group and a methanesulfonyloxy group.
Further, the amines represented by the above general formula (III) which are starting materials for preparing the compounds of the present invention can be commercially available compounds or compounds which can be synthesized by using ordinary chemical synthesis procedures, and these amines may be used in a free form or in a form of a salt which does not adversely affect the reaction. Salts of the amines (III) which can be used include salts of inorganic or organic acids, for example, a hydrogen halide such as hydrogen chloride or hydrogen bromide, sulfuric acid, acetic acid, and p-toluenesulfonic acid.